Carmustine Wafer in Combination With Retifanlimab and Radiation With/Without Temozolomide in Subjects With Glioblastoma

Inclusion Criteria:

• Newly-diagnosed adults with WHO (World Health Organization) Grade IV Glioblastoma orgliosarcoma based on histopathological or molecular criteria who had carmustinewafers placed at resection

• No prior treatment for GBM other than surgical resection and carmustine waferplacement (Patients who had a biopsy prior to resection are allowed)

• Post-operative MRI or CT scan within 72 hours (preferably 24 hours) of surgicalresection

• Substantial recovery from surgical resection

• On a stable or decreasing dose of steroids

• Karnofsky Performance Status of ≥ 60

• Clinically appropriate for concomitant temozolomide plus radiation therapy (RT)based on institutional guidelines

• Age ≥18 years

• Ensure that pregnant or lactating females are not enrolled and that contraceptiverequirements are in accordance with applicable and recent requirements.

• Men must agree to take appropriate precautions to avoid fathering children (with atleast 99% certainty) from screening through 180 days after the last dose ofretifanlimab

• Must have normal organ and marrow function on routine laboratory tests

• Ability to understand and the willingness to sign a written informed consentdocument

• Subjects must be willing and able to comply with scheduled visits, treatmentschedule, study procedures, and other requirements of the study

Exclusion Criteria:

• Recurrent glioblastoma (GBM) or progression of lower grade tumor

• Central nervous system (CNS) hemorrhage of Grade > 1 on baseline MRI scan, unlesssubsequently documented to have resolved

• Any known metastatic extracranial or leptomeningeal disease

• Intent to use other anti-neoplastic medications/treatments including the Optune®device

• Any serious or uncontrolled medical disorder that, in the opinion of theinvestigator, may increase the risk associated with study participation or studydrug administration, impair the ability of the subject to receive protocol therapy,or interfere with the interpretation of study results

• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4antibody or any other antibody or drug specifically targeting T-cell co-stimulationor immune checkpoint pathways

• Active, known or suspected autoimmune disease, with the following exceptions:Subjects with type I diabetes mellitus, hypothyroidism only requiring hormonereplacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiringsystemic treatment (subjects with a history of flares requiring systemic treatmentare excluded), or other autoimmune conditions not expected to recur in the absenceof an external trigger are permitted to enroll

• Subjects with history of life-threatening toxicity, including hypersensitivityreaction, related to prior immunoglobulin treatment for another condition (exceptthose considered unlikely to re-occur, with written approval of study PI) or anyother study drug component

• History or evidence upon physical/neurological examination of other central nervoussystem condition (e.g., seizures, abscess) unrelated to cancer, unless adequatelycontrolled by medication or considered not potentially interfering with protocoltreatment

• Surgical procedure < 7 days prior to study treatment (No restriction for insertionof a central venous access device)

• Unable to swallow oral medication or any gastrointestinal disease or surgicalprocedure that may seriously impact the absorption of temozolomide

• Prior malignancy active within the previous 3 years except for locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,totally excised melanoma of stage IIA or lower, low or intermediate-grade localizedprostate cancer (Gleason score ≤ 7), and curatively-treated carcinoma in situ of thecervix, breast, or bladder.

• Known history of any positive test for hepatitis B virus or hepatitis C virusindicating acute or chronic infection, and/or detectable virus

• Known history of positive test for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

• Evidence of interstitial lung disease, history of interstitial lung disease, oractive, noninfectious pneumonitis.

• Palliative radiation therapy administered within 1 week of first dose of studytreatment or radiation therapy in the thoracic region that is > 30 Gy within 6months of the first dose of study treatment. Note: Participants must have recoveredfrom all radiation-related toxicities (to Grade >1 or baseline), not requirecorticosteroids for this purpose, and not have had radiation pneumonitis.

• Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline (with theexception of any grade of alopecia and anemia not requiring transfusion support).

• Participants with specified abnormal laboratory values at screening

• Active autoimmune disease requiring systemic immunosuppression in excess ofphysiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone orequivalent).

• Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day ofprednisone or equivalent for adrenal or pituitary insufficiency and in theabsence of active autoimmune disease is permitted.

• Participants with asthma that requires intermittent use of bronchodilators,inhaled steroids, or local steroid injections may participate.

• Participants using topical, ocular, intra-articular, or intranasal steroids (with minimal systemic absorption) may participate.

• Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy)or study treatment-related standard premedication is permitted.

• Has an active infection requiring systemic antibiotics or antifungal treatment

• History of organ transplant, including allogeneic stem cell transplantation

• Known allergy or hypersensitivity to any component of retifanlimab or formulationcomponents

• Has received a live vaccine within 28 days of the planned start of study drug (Note:Examples of live vaccines include but are not limited to measles, mumps, rubella,chicken pox/zoster, yellow fever, rabies, Bacillus of Calmette and Guerin (BCG), andtyphoid vaccine. Inactivated seasonal influenza vaccines and COVID-19 vaccine(s) arepermitted and do not require a 4-week waiting period before starting studytreatment; however, intranasal influenza vaccines are live attenuated vaccines andare not allowed.)

• Patients who are taking Probiotic dietary supplements

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations (e.g. prisoners/involuntarilyincarcerated individuals) that would limit compliance with study requirements